A large percentage of individuals who are dependent on amphetamine (amph), abuse other drugs. The most frequent pattern of polydrug abuse involves the conjoint use of amph and drugs with anxiolytic and/or sedative properties-i.e., benzodiazepines (BZs) and alcohol. Polydrug abusers are more difficult to treat due to complications which arise during detoxification involving multiple substances, and they are more likely to experience trauma, accidents, and disruptions in their family, work, and social environment. The broad, long-term objectives of this research then, are to identify biological factors which underlie this pattern of polydrug abuse. The role of GABA in amph use has not been studied extensively. In addition to its rewarding properties, amph intoxication is associated with a sense of anxiety and tension. Ligands that bind to the GABA-A/BZ receptor complex play a central role in anxiety. Drugs like alcohol and BZs, which exert some of their effects through the GABA-A/BZ receptor complex, appear to reduce the anxiogenic effects of amph-this may provide an incentive for their use. The specific aims of this research are to: (1) Study the effects of acute amph on behavior and GABA-A receptor binding. We will: a) examine the time-course of the effects of acute amph; and b) determine whether the effects of acute amph on behavior and GABA-A receptor binding are mediated through the GABA-A/BZ receptor complex; (2) Study the effects of repeated intermittent exposure to amph on behavior and GABA-A receptor binding. We will: a) determine whether repeated exposure leads to the development of tolerance with respect to the behavioral and receptor changes seen following acute challenge; b) determine whether reinstatement of the anxiogenic behavioral response following a dose escalation in preexposed animals is mediated through the GABA-A/BZ receptor complex; c) examine the duration of the effects of preexposure to amph; and (3) Examine the effects of amph on BZ receptor binding. We will: a) examine the time-course of the effects of acute amph; b) determine whether repeated exposure leads to the development of tolerance with respect to the receptor changes seen following acute challenge.